Heparin and nonanticoagulant heparin preserve regional myocardial contractility after ischemia-reperfusion injury: role of nitric oxide.
OBJECTIVE
These studies were performed to determine the effect of heparin and nonanticoagulant heparin on myocardial function after ischemia-reperfusion and to further evaluate the role that the nitric oxide-cyclic guanosine monophosphate pathway plays in mediating the effect of heparin.


METHODS
Fifteen dogs were subjected to 15 minutes ischemia followed by 120 minutes reperfusion and pretreated with either saline solution, bovine heparin (6.0 mg/kg intravenously), or N-acetyl heparin (6.0 mg/kg intravenously), a heparin derivative without anticoagulant properties. The left anterior descending artery was occluded for 15 minutes and regional systolic shortening, a unitless measure of myocardial contractility, assessed during reperfusion. To evaluate the role of nitric oxide, the inhibitor N(omega)-nitro-L-arginine, 1.5 mg/kg intracoronary, was given before heparin administration. Myocardial levels of cyclic guanosine monophosphate, the second messenger of nitric oxide, were also measured in the N-acetyl heparin group using radioimmunoassay.


RESULTS
Regional systolic shortening was significantly decreased in the saline group during 60 and 120 minutes compared with before ischemia (9.2 +/- 1.0 and 9.0 +/- 0.9 vs 12.2 +/- 1.2, p < or = 0.0003). Heparin and N-acetyl heparin-treated dogs, however, showed preservation of systolic shortening throughout reperfusion. Administration of nitro-L-arginine significantly attenuated the protective effect of heparin (9.2 +/- 1.2 vs 12.7 +/- 1.1, p < or = 0.0001) and N-acetyl heparin (9.3 +/- 0.3 vs 12.8 +/- 0.4, p < or = 0.0001) during 120 minutes reperfusion. Myocardial levels of cyclic guanosine monophosphate were also significantly increased in the N-acetyl heparin group compared with saline (199.1 +/- 7.1 vs 103.5 +/- 4.5 pmol/mg, p < or = 0.0001).


CONCLUSIONS
Heparin preserves myocardial contractility after ischemia-reperfusion independent of its anticoagulant properties. Furthermore, the protective effects of heparin during ischemia-reperfusion are mediated, at least in part, through a nitric oxide-cyclic guanosine monophosphate pathway.
Kouretas
P C
PC
Department of Surgery, Georgetown University Medical Center, Washington, DC, USA.
Myers
A K
AK
Kim
Y D
YD
Cahill
P A
PA
Myers
J L
JL
Wang
Y N
YN
Sitzmann
J V
JV
Wallace
R B
RB
Hannan
R L
RL
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects; D019335:Nitroarginine / Q000494:pharmacology; D013997:Time Factors
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D006493:Heparin; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP